Rothman, A.M. orcid.org/0000-0002-7847-4500, Arnold, N., Pickworth, J. et al. (10 more authors) (2016) MicroRNA-140-5p and SMURF1 Regulate Pulmonary Arterial Hypertension. Journal of Clinical Investigation, 126 (7). pp. 2495-2508. ISSN 1558-8238
Abstract
Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment-naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-5p mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-5p target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-5p and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 American Society for Clinical Investigation. Reproduced in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number BRITISH HEART FOUNDATION FS/13/48/30453 BRITISH HEART FOUNDATION PG/11/116/29288 MEDICAL RESEARCH COUNCIL G0800318/1 MEDICAL RESEARCH COUNCIL MR/K002406/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 15 Aug 2016 14:26 |
Last Modified: | 15 Aug 2016 14:26 |
Published Version: | http://dx.doi.org/10.1172/JCI83361 |
Status: | Published |
Publisher: | American Society for Clinical Investigation |
Refereed: | Yes |
Identification Number: | 10.1172/JCI83361 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:103672 |